This proposal will investigate the association between subgingival microbial community composition and insulin resistance. This will be accomplished among 300 diabetes-free participants enrolled in the PI's NIH funded R00 career development award: The Oral Infections, Glucose Intolerance and Insulin Resistance Study (ORIGINS). Type 2 diabetes mellitus is an important public health problem and chronic infections, including periodontal infections, have been suggested as a potential risk factor for insulin resistance and diabetogenesis. However the temporality and mechanism(s) of reported associations are unclear. Our work has brought some clarity to the topic by demonstrating that periodontal infections predict both incident diabetes as well as the progression of hemoglobin A1c (HbA1c) among healthy, diabetes-free participants. These represent the first studies to report on longitudinal associations between a chronic infection and risk for diabetes development. However, our previous studies were based on clinical measures and did not study oral microbial community characteristics directly. Therefore we propose to use both a microbe identification microarray and 454 pyrosequencing methods to directly study the microbial composition of biofilm samples collected from diabetes-free participants. ORIGINS is a multi-ethnic sample of working men and women aged 20 - 55 years with membership in the SEIU1199 union at Columbia University Medical Center, in New York City. Results from this study will identify specific microbial community characteristics associated with insulin resistance both cross-sectionally and longitudinally. In doing so, we will have critical knowledge for focused a priori hypothesis testing during the planned long term follow-up of the ORIGINS cohort to evaluate whether microbial community characteristics observed to be related to insulin resistance in the present study can also predict the development of clinical type 2 diabetes. Moreover, in the near-term these findings can also inform the appropriate eligibility criteria and therapy targets fr small focused intervention trials to investigate whether anti-infective periodontal therapy can reduce insulin resistance in at-risk individuals. PUBLIC HEALTH RELEVANCE: The identification of a role for periodontal bacteria in the development of T2DM could have substantial public health impact. Even modest increases in T2DM risk associated with periodontal infection would be important given the high prevalence of treatable and preventable periodontal infections. The existence of an infrastructure for prevention and treatment of oral infection could allow for rapid translation of findings into both medical and dental clinical practice as well as public health policy.